Pathophysiologic And Genetic Features

The first step in the telangiectasia formation consists a focal dilatation of postcapillary venules with predominant stress fibers in pericytes along the luminal border. As the venules enlarge, they become convoluted and form excessive layers of smooth muscle cells without elastic fibers and connect directly with the dilated arterioles.1-1-1

The molecular basis consists of a defect of the TGF-p signaling pathway which, in normal conditions, plays an important role in vascular remodeling and maintenance of vessel wall integrity.1-2-1 The genes responsible for HHT, endoglin and ALK-1 represent a coreceptor and a type 1 TGF-p receptor, respectively. In particular, endoglin is a homodimeric transmembrane glycoprotein expressed predominantly in endothelial cells and is composed of disulfide-linked 90-kDa subunits with large extracellular domains and serine/threonine-rich cytoplasmic regions without consensus signaling motifs. Thus far, numerous mutations of ENG gene have been described and these mutations tend to be unique and family specific.[3,4]

ALK-1 has the characteristics of a Type 1 serine-threonine kinase receptor; in vitro, it binds to activin or TGF-p types 1, 2, and 3, but the natural ligand in vivo is unknown. ALK-1 mutations include insertions, deletions, and nonsense mutations and, as in endoglin, several of these mutations give rise to an unstable protein. Both ALK-1 and endoglin have been suggested to trigger HHT according to the haploinsufficiency model.[5-7]

The exact mechanism by which mutations of endoglin and ALK-1 induce the diffuse angiodysplasia is poorly understood. The transmission of the TGF-p signals from the cell surface to the nucleus requires a complex system of receptors and cytosolic Smad proteins. Endoglin modulates this transmission, forming a complex with TGF-p1 and TGF-p2 receptors on the endothelial cells. Upon association with type 2 TGF-p, the receptor endoglin is phosphorylated. The association with TGF-p2 receptor results in an increased phosphorylation of type

1 TGF-p receptor which, in turn, phosphorylates Smad2. This activated complex associates with Smad4 and, entering the nucleus, regulates the transcription of the target genes.

A balance model for the role of ALK and endoglin in angiogenesis has been proposed. Activation of ALK-1 leads to the endothelial cell (EC) resolution phase where angiogenic factors, such as the vascular endothelial growth factor (VEGF), are repressed; when the TGF-p1 signal is mediated by ALK-5, it transforms ECs into the activation phase of angiogenesis. The ALK-1 pathway is disrupted in HHT type 2, leading to the dominance of the ALK-5 signaling route, thus stimulating the activation phase of ECs and resulting in arteriovenous connections between dilated venules and arteries. In HHT type 1 a reduced dosage of endoglin may give a significant decrease in TGF-p1 concentration, impairing the ALK-1 and ALK-5 pathways. Therefore, having a higher sensitivity to TGF-p1 than ALK-1, ALK-5 pathway predominates and induces the arteriovenous connec-tions.[2] According to the proposed model, the overexpression of several vascular growth factors, such as VEGF, would result from an aberrant angiogenic signal in HHT and might participate in the formation and enlargement of the vascular malformations. In fact, in our recent study, we demonstrated increased levels of VEGF in the serum of HHT patients, in agreement with the VEGF stimulation synthesis proposed in the murine model.[8]

Recently, ALK-1 signaling has been demonstrated to have a role in arterialization and remodeling of arteries so that the arterioles rather than the venules are the primary vessels affected by the loss of an ALK-1 allele. Thus, contrary to the current view of HHT as a venous disease, the arterioles rather than the venules are the primary vessels affected by the loss of an ALK-1 allele.[9]

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